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Datopotamab Deruxtecan Demonstrated Meaningful Clinical Activity in Patients with Previously Treated Advanced EGFRMutated Non-Small Cell Lung Cancer in TROPION-Lung05 and TROPION-Lung01 Pooled Analysis

On December 6, 2024 Daiichi Sankyo reported that pooled analysis of the TROPION-Lung05 phase 2 and the TROPION-Lung01 phase 3 trials showed datopotamab deruxtecan (Dato-DXd) demonstrated clinically meaningful tumor response in patients with previously treated advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) (Press release, Daiichi Sankyo, DEC 6, 2024, View Source [SID1234648838]). These data, along with progression-free and overall survival results from the analysis, were presented during a late-breaking proffered paper session (LBA7) at the 2024 ESMO (Free ESMO Whitepaper) Asia (#ESMOAsia24) Congress.

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Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

Datopotamab deruxtecan demonstrated a confirmed objective response rate (ORR) of 42.7% (95% confidence interval [CI]: 33.6-52.2) in a pooled analysis of 117 patients with EGFR-mutated NSCLC from the TROPION-Lung05 (n=78) and TROPION-Lung01 (n=39) trials, as assessed by blinded independent central review (BICR). Five (4.3%) complete responses (CRs), 45 (38.5%) partial responses (PRs) and 48 (41.0%) cases of stable disease (SD) were observed. The median duration of response (DOR) was 7.0 months (95% CI: 4.2-9.8) and the disease control rate (DCR) was 86.3% (95% CI: 78.7- 92.0). Median progression-free survival (PFS) was 5.8 months (95% CI: 5.4-8.2) and median overall survival (OS) was 15.6 months (95% CI: 13.1-19.0).

"Initial treatment with EGFR tyrosine kinase inhibitors has significantly improved outcomes for patients with advanced EGFR-mutated non-small cell lung cancer, but most patients eventually experience disease progression," said Myung-Ju Ahn, MD, PhD, Professor, Hematology-Oncology Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

"These results suggest datopotamab deruxtecan could offer patients with EGFR-mutated non-small cell lung cancer a much-needed option in the pre-treated metastatic setting."

Results in patients previously treated with osimertinib were similar to the overall pooled population. In 96 patients previously treated with osimertinib, a confirmed ORR of 44.8% (95% CI: 34.6-55.3), as assessed by BICR was seen. Four (4.2%) CRs, 39 (40.6%) PRs and 37 (38.5%) cases of SD were observed. The median DOR was 6.9 months (95% CI: 4.2-9.8) and the DCR was 85.4% (95% CI: 76.7-91.8). Median PFS was 5.7 months (95% CI: 5.4-7.9) and median OS was 14.7 months (95% CI: 13.0-18.3).

"Results of this pooled analysis show the potential for datopotamab deruxtecan in patients with EGFRmutated non-small cell lung cancer with disease progression following multiple lines of prior treatment in the metastatic setting," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "The data from the TROPION-Lung05 and TROPION-Lung01 trials support our recent regulatory submission in the U.S. and highlight the potential of datopotamab deruxtecan to become a new treatment option for this patient population."

"These results show that datopotamab deruxtecan can improve outcomes for patients with EGFR-mutated non-small cell lung cancer whose disease has become resistant to current treatments, and that it has potential to do so in patients harboring a range of EGFR mutations," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "These data, as well as our forthcoming trial in patients with TROP2-QCS biomarker-positive tumors, mark critical steps in our effort to follow the science and understand the full potential of datopotamab deruxtecan in later-line lung cancer settings."

Patients in the pooled analysis received a median of three prior lines of treatment in the metastatic setting (range, 1-5). Eighty-two percent of patients were previously treated with osimertinib, including 40.2% in the first line and 29.1% in the second line.

In the pooled population, a range of EGFR mutations was observed, including exon 19 del, exon 21
L858R, exon 20 T790M, exon 18 G719X, exon 21 L861Q, exon 20 ins, and exon 20 C797S.
Summary of Pooled Results from TROPION-Lung05 and TROPION-Lung01
Efficacy Measure EGFR-mutated Pool
(n=117)
Prior Osimertinib
(n=96)
Confirmed ORR, n (%) [95% CI]
i,ii 50 (42.7%) [33.6-52.2] 43 (44.8%) [34.6-55.3]
Median BOR, n (%)i
CR, n (%) 5 (4.3%) 4 (4.2%)
PR, n (%) 45 (38.5%) 39 (40.6%)
SD, n (%) 48 (41.0%) 37 (38.5%)
Non-CR/Non-PD, n (%) 3 (2.6%) 2 (2.1%)
PD, n (%) 12 (10.3%) 10 (10.4%)
NE, n (%) 4 (3.4%) 4 (4.2%)
Median DOR, months (95% CI)i 7.0 months (4.2-9.8) 6.9 months (4.2-9.8)
DCR, n (%) (95% CI) i, iii 101 (86.3%) [78.7-92.0] 82 (85.4%) [76.7-91.8]
Median PFS, months (95% CI)i 5.8 months (5.4-8.2) 5.7 months (5.4-7.9)
Median OS, months (95% CI) 15.6 months (13.1-19.0) 14.7 months (13.0-18.3)

About TROPION-Lung05

TROPION-Lung05 is a global, multicenter, single-arm, open-label phase 2 trial evaluating the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC with actionable genomic alterations who have progressed on at least one TKI (with or without other systemic therapies) and on or after one regimen of platinum-based chemotherapy. Patients receiving up to four prior lines of treatment with tumors with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET or MET were eligible for the trial.

The primary trial endpoint of TROPION-Lung05 is ORR as assessed by BICR. Secondary efficacy endpoints include DoR, DCR, clinical benefit rate (CBR), PFS, time to response (TTR), OS and safety.

TROPION-Lung05 enrolled 137 patients globally in Asia, Europe and North America. For more information visit ClinicalTrials.gov.

About TROPION-Lung01

TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, TTR, and DCR as assessed by both BICR and investigator, and safety. TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America.

For more information visit ClinicalTrials.gov. Primary PFS results and interim OS results from TROPION-Lung01 were presented at the 2023 ESMO (Free ESMO Whitepaper) (#ESMO23) Congress. Final OS results were presented at IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and simultaneously published in the Journal of Clinical Oncology in September 2024.

About Advanced Non-Small Cell Lung Cancer

Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.1 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about 80% of cases.2 Approximately 10% to 15% of patients with NSCLC in the U.S. and Europe, and 30% to 40% of patients in Asia have an EGFR mutation.3,4 The majority of EGFR mutations occur in tumors of nonsquamous histology.

For patients with tumors that have an EGFR mutation, the established first-line treatment in the metastatic setting is an EGFR TKI.6 While EGFR TKIs have improved outcomes in the first-line setting, most patients eventually experience disease progression and receive subsequent therapies, such as chemotherapy.7,8,9,10 TROP2 is a protein broadly expressed in the majority of NSCLC tumors.11 There is currently no TROP2 directed ADC approved for the treatment of lung cancer.

About Datopotamab Deruxtecan (Dato-DXd)

Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 low or negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

Monopar Announces First Patient Dosed with its Novel Therapeutic Radiopharmaceutical MNPR-101-Lu

On December 5, 2024 Monopar Therapeutics Inc. (Nasdaq: MNPR), a clinical-stage biotechnology company focused on developing innovative treatments for patients with unmet medical needs, reported the first patient ever dosed with MNPR-101-Lu (Press release, Monopar Therapeutics, DEC 5, 2024, View Source [SID1234648854]). This novel therapeutic radiopharmaceutical combines MNPR-101, Monopar’s antibody that selectively targets the urokinase plasminogen activator receptor (uPAR), with the therapeutic radioisotope lutetium-177. uPAR is involved in tumor growth and metastasis, and is found in some of the most aggressive, deadly cancers, including pancreatic, ovarian, triple negative breast, and colorectal cancers.

The MNPR-101-Lu intravenous infusion was well-tolerated with no serious adverse reactions reported. This patient, dosed under a compassionate use protocol in the US, has metastatic pancreatic cancer, and prior to dosing, the cancer was imaged using MNPR-101-Zr (a zirconium-89 imaging radioisotope conjugated to MNPR-101) with a PET/CT scanner and showed uPAR expression.

"As a result of encouraging biodistribution and dosimetry clinical data we recently reported (link) with our radiodiagnostic, MNPR-101-Zr, we have been eagerly looking forward to initiating treatment of patients with MNPR-101-Lu, hopeful it may provide an important therapeutic benefit to a group of cancer patients very much in need," said Chandler Robinson, MD, Monopar’s Chief Executive Officer.

"We are thrilled to have dosed this patient with MNPR-101-Lu, and believe this may be the world’s first dosing of a patient with a uPAR-targeted therapeutic radiopharmaceutical," said Andrew Cittadine, Monopar’s Chief Operating Officer.

Monopar is actively enrolling participants in two Phase 1 clinical studies in Australia, evaluating MNPR-101-Zr for imaging and MNPR-101-Lu for treatment of advanced solid tumors. Further information about the MNPR-101-Lu Phase 1a trial is available at www.ClinicalTrials.gov under study identifier NCT06617169. Further information about the MNPR-101-Zr Phase 1 imaging and dosimetry clinical trial is available at www.ClinicalTrials.gov under study identifier NCT06337084.

Simcha Therapeutics Announces the Opening of Two Clinical Studies Exploring ST-067 in Hematological Indications

On December 5, 2024 Simcha Therapeutics ("Simcha"), a clinical-stage immunobiology company pioneering first-in-class cytokine treatments in cancer, reported the opening of two clinical studies assessing the use of ST-067, Simcha’s decoy-resistant IL-18, in hematological indications (Press release, Simcha Therapeutics, DEC 5, 2024, View Source [SID1234648850]). One study (ClinicalTrials.gov ID NCT06492707) will assess ST-067 in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), while the other study (ClinicalTrials.gov ID NCT06588660) will test ST-067 in combination with teclistamab (TECVAYLI) in patients with multiple myeloma.

"These two studies, both of which may rapidly generate clinical proof-of-concept data in indications where there is significant need for better therapies, represent a very exciting opportunity for us to explore additional therapeutic areas that have great potential to respond well to treatment with IL-18," said Sanuj Ravindran, M.D., chief executive officer of Simcha. "Emerging data, including those included in our preclinical poster to be presented at ASH (Free ASH Whitepaper), are generating signals that serve as proof-of-concept and point to the therapeutic potential of IL-18 across various hematological cancers, so we are pleased to partner with leading hematologic cancer experts on these trials."

The AML/MDS study, under principal investigator Elizabeth Krakow, M.D., of Fred Hutch Cancer Center, is enrolling patients over 18 years of age who have persistent or recurrent AML or MDS after hematopoietic cell transplantation (HCT), also known as a bone marrow transplant. While HCT is the only curative therapy for most forms of AML or MDS, relapse occurs in approximately one-third of patients and is the most common cause of death following HCT.

The Phase 1, open-label, dose-escalation study will primarily assess dose limiting toxicities and the number of clinical trial subjects who complete four consecutive weeks of treatment with ST-067. Secondary endpoints will assess response rates, overall survival and whether graft-versus-leukemia effects can be elicited without the accompanying graft-versus-host disease.

The study assessing ST-067 in combination with teclistamab, a bi-specific antibody with T cell engagement activity, in patients 18 years of age or older with relapsed or refractory multiple myeloma is occurring under the direction of Rahul Banerjee, M.D., of the University of Washington and Fred Hutch Cancer Center. This open-label Phase 1b study will primarily assess dose-limiting toxicities of ST-067 alone and in combination with teclistamab, as well as optimal dosing and the incidence of adverse events. Secondary endpoints will include overall response rate, duration of response, progression-free survival, overall survival and measurable residual disease negativity.

T-cell directed therapeutics, like teclistamab, other bi-specific antibodies or CAR Ts, have become standards of care for the treatment of relapsed/refractory multiple myeloma. However, they are not curative, as not all patients respond to teclistamab, and relapse can occur in those that do. The multiple myeloma study is based on the hypothesis that ST-067 in combination with teclistamab will promote T-cell fitness and persistence, which could increase the number of patients who respond to teclistamab and lengthen durations of response.

Data to be highlighted at ASH (Free ASH Whitepaper) in a poster presentation demonstrate the therapeutic activity of decoy-resistant IL-18 in multiple mouse models of hematological tumors including B-cell lymphoma, acute myeloid leukemia and plasma cell myeloma. The poster, entitled "Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies" will be presented during poster session 802 on Monday, December 9 from 6:00 PM to 8:00 PM.

In addition, a trials in progress poster describing the AML/MDS study will be presented at ASH (Free ASH Whitepaper). The poster, entitled "Trials in Progress: Decoy-Resistant Interleukin-18 (DR-18) for Relapse or Pre-Emptive Treatment of Measurable Residual Disease after Allogeneic Hematopoietic Cell Transplantation in Patients with AML and MDS: DR. DREAM, a Phase I Trial (NCT06492707)" will be presented Monday, December 9 from 6:00 PM to 8:00 PM in poster session 701.

Sarah Cannon Research Institute to Showcase Latest Research Insights at the 2024 ASH Annual Meeting & Exposition

On December 5, 2024 Sarah Cannon Research Institute (SCRI) reported that more than 65 abstracts and presentations have been accepted for the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, Sarah Cannon Research Institute, DEC 5, 2024, View Source [SID1234648849]). Hosted in San Diego, Calif., and online from Dec. 7-10, the event is recognized as the premier global hematology conference, drawing experts and researchers from around the world.

SCRI investigators, including physicians from The US Oncology Network and HCA Healthcare Sarah Cannon Transplant & Cellular Therapy Network, will present pioneering research across a range of topics including malignant and non-malignant blood cancers, blood disorders, CAR T-Cell therapy, innovative immunotherapies and real-world outcomes with a specific focus on results between inpatient and outpatient care.

"We look forward to presenting our latest research findings, which include advancements in the treatment of a wide range of hematologic malignancies," said David Spigel, MD, Chief Scientific Officer for SCRI. "This year’s presentations are a testament to the collective efforts of investigators across our network, highlighting the power of collaboration in advancing clinical research."

Featured presentations include:

Tonya Cox, BSN, HCA Healthcare Sarah Cannon Transplant & Cellular Therapy Network (SCTCTN), is first author alongside thirteen SCTCTN co-authors on a poster presentation titled, "Comparison of 15- Vs. 30-Day Remote Patient Monitoring for Outpatient Chimeric Antigen Receptor T-Cell Therapy across a Large Health System" to be shared on Saturday, December 7 at 5:30 p.m. PST.

Navneet Majhail, MD, MS, FASTCT, Physician-in-Chief of Blood Cancers for HCA Healthcare Sarah Cannon Cancer Network, and five SCTCTN physicians are co-authors on an oral presentation titled, "Efficacy and Safety of Brexucabtagene Autoleucel for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Patients Aged 60 and Above." The oral presentation takes place on Sunday, December 8 at 9:30 a.m. PST.

Minoo Battiwalla, MD, SCRI at TriStar Centennial, is first author alongside eleven SCTCTN co-authors on a poster presentation titled, "The Patient Journey and Treatment Outcomes Comparing Inpatient Versus Outpatient Axicabtagene Ciloleucel in Non-Hodgkin’s Lymphoma – a Large, Multicenter Study" to be shared on Sunday, December 8 at 6:00 p.m. PST.

Jeff P. Sharman, MD, SCRI at Willamette Valley Cancer Institute & Research Center is first author alongside co-author John M. Burke, MD, SCRI at Rocky Mountain Cancer Centers on an oral presentation titled, "BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma." The oral presentation will take place on Monday, December 9 at 3:30 p.m. PST.

Haydar Frangoul, MD, SCRI at TriStar Centennial Children’s Hospital, is first author on a poster presentation titled, "Durable Clinical Benefits with Exagamglogene Autotemcel for Severe Sickle Cell Disease" to be shared on Monday, December 9 at 6:00 p.m. PST.

Mission Bio Showcases Critical Insights Into Multiple Myeloma, AML MRD, CAR-T Safety & Integrated Single-Cell DNA and Fusion Profiling at the 2024 ASH Annual Meeting

On December 5, 2024 Mission Bio, a leader in single-cell multiomics solutions for precision medicine, reported the full list of presentations by leading researchers and clinicians spanning multiple indications of blood cancer, leveraging the Tapestri Platform to advance therapeutic research and development at the 66th ASH (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Mission Bio, DEC 5, 2024, View Source [SID1234648848]). More than 20 presentations at the event, which takes place Dec. 7-10 in San Diego, will shine a spotlight on how Mission Bio’s customers are using Tapestri and associated products to gain a broader and deeper understanding of Multiple Myeloma, AML, Lymphoma, and CAR-T therapy development.

Among these presentations, Mission Bio will showcase new datasets for the first time, demonstrating how the Tapestri Single-cell Multiple Myeloma Multiomics Solution, which became commercially available this year, can be used to integrate genomic, immunophenotypic, and clonotypic assessment to pinpoint disease-driving clones in Multiple Myeloma (MM). The team behind the data was led by Mission Bio CTO and co-founder Adam Sciambi.

"Our ongoing mission is to provide scientists with the means to understand hard-to-treat diseases like MM in ways that will lead to new, more effective treatments," Sciambi said. "We’re looking forward to sharing our findings on the role of rare clones in the progression from precursor conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to full-blown MM, as well as the comprehensive clonal architecture underlying relapse and treatment resistance. We’re equally excited to see what our customers are doing to advance research into other forms of cancer."

A new study from Heidelberg University Hospital will showcase the value of single-cell DNA+protein multiomics sequencing to refine minimal residual disease (MRD) assessment in acute myeloid leukemia (AML). Presented under the title "Clonal Dynamics of Leukemic and Clonal Hematopoiesis Mutations Predict Relapse in Single Cell MRD Analysis of AML in First Complete Remission," the research uses patient samples to demonstrate how this approach offers greater precision than current techniques, potentially establishing a way to redefine AML MRD.

Researchers from the University of Cincinnati will also introduce the first-ever data demonstrating the feasibility of integrating DNA and fusion profiling at the single-cell level as a multiomic approach. The presentation, titled "Single-Cell Multi-Omic Analysis of KMT2A-Rearranged Pediatric Acute Leukemia Clonal Evolution," is the first of its kind to utilize the combination of simultaneous molecular profiling and fusion identification at the single-cell level for pediatric leukemia.

Following a recent publication in the New England Journal of Medicine, new findings from Stanford University highlight the power of single-cell DNA sequencing to uncover critical genomic insights in chimeric antigen receptor (CAR) T-cell therapy, revealing myeloid predominance for TP53 clonal hematopoiesis in post-CAR therapy myeloid neoplasms (tMN) among non-Hodgkin lymphoma patients. These findings, presented under the title "Single Institution Analysis of Lymphoma Treatment Related Post-CAR Myeloid Neoplasms," underscore the potential of single-cell DNA sequencing to inform CAR T therapy development, enabling safer treatments by addressing risks tied to therapy-induced molecular changes.

Additional institutions included among the presentations at ASH (Free ASH Whitepaper) include the National Institutes of Health, Weill Cornell Medical College, University of Pennsylvania, Berlin Institute of Health, Oxford University Hospitals, University of Miami Miller School of Medicine, and University of Toronto. For the full list of poster and oral presentations, or to schedule a one-on-one meeting with the Mission Bio team at the 2024 ASH (Free ASH Whitepaper) Annual Meeting, please visit View Source Attendees can also learn more about the Tapestri Platform and all of Mission Bio’s multiomics solutions by visiting booth #2112.